Production of compounds of the



United States Patent ce m, f jfflij sults in good yields of pure end products; it is simpler 2,917,523 than the processes hitherto known (see for example PRODUCTION OF COMPOUNDS OF THE Fortschritte der Chemie organischer Naturstofle, VITAMlN A SERIES SpringerVerlag, Vienna, 1952, volume IX, pages 56 et 5 seq.) and, contrary to known rocesses see the review Horst F Ludwlgshaf? (Rhmehanli Georg W given by H. O. Huisman et 51. Recueil des Travaux Tubmgenhcermfmy magnets to Baihsche & Chimiques des Pays-Bas vol 71 (1952) p 911) gives Soda-Fabrik Aktrengesellsehaft, Ludwlgshafen (Rhine), no ,,retro rearrangement;, of'the conjugte system of Germany double bonds. The products obtainable according to the No Drawing. Application July 27, 1956 present invention, such as vitamin A, vitamin A acid, Serial No. 600,404 vitamin A ether and axerophthene, are known to be valuable pharmaceutical products.

Claims riori a lication Ger an All st3 1955 p pp m y The following examples will further illustrate this in- 5 Claims. (Cl. 260410.9) vention but the invention is not restricted to these examples. The parts specified are parts by weight. This invention relates to an improved process for the Example 1 production of compounds of the vitamin A series.

We have found that compounds of the vitamin A series sob-mom of 18 parts of phosphorus mbromlde m are obtained by reacting a beta-ionyl halide with a tertiary 9 B of absolut? ether is gradually introduced While phosphine, for example triphenyl phosphine, to form 20 stirring mto a solution of 20 parts of pure beta-ionol (see quaternary phosphonium halide, reacting this, prefer- Inhofien, B9hlmann and Bohlmann, ably in dimethylformamide solution, with about an equiv- 565 (1949) 35) 01 of absolute ether at alent amount of a compound capable of binding hydroto After stlmng for 12 hours a! room gen halide, as for example an alkali or alkaline earth temperature mlxture 1s Poured OHIO ice and the metal alcoholate or an alkali metal acetylide or amide ethereal layer decanted OE and Washed Well With to form the betadonylidene phosphine ylide, allowing an water. The ether solution is dried for 2 hours with calaldehyde of the general formula cium chlorlde and then concentrated somewhat under reduced pressure. After adding 22 parts of triphenyl phos- O=CH CH=CH C(CH3)=CH R phine, it is stirred for 5 hours at room temperature. The

(in which R is a lower alkyl, carboxylic acid e ter or a solvent is then distilled olf and the residue heated to 80 CH OH group which may be etherified or esterified) to 10 900 in Water-let Vacuum for 30 milluts- The act thereon, and separating the phosphine oxide formed phosphonium bromide, which partly crystallizes, is disas a byproduct. solved in 150 parts of dimethylformamide and while stir- When using beta-ionyl bromide, triphenyl phosphine, ring at room temperature 4.5 parts of finely powdered sodium acetylide and 4-methyl-hexadiene-(2.4)-al-(l)- sodium acetylide are added. The mixture immediately acid-(6)-ethyl ester as initial materials, the reaction may becomes reddish-brown and the beta-ionylidene-triphenyl- Instead of triphenylphosphine other tertiary phosphines, 0 20 C., a solution of 5 parts of 4-methylhexadiene-(2.4)- in particular triarylphosphines, such as tri-p-tolyl-, pal-(l)acid-(6)-ethyl ester in 15 parts of dimethylformtolyl-diphenyl-, tri(chlorophenyl)- or naphthyl phenyl amide is added. A slight rise in temperature occurs; it is phosphines are suitable. Instead of beta-ionyl bromide stirred for another 2 hours, added to a mixture of ice and there may be used beta-ionyl chloride or iodide. Instead 10% phosphoric acid and extracted with petroleum ether. of 4-methylhexadiene-(2.4)-al-(l) acid-(6)-ethylester 5 The pale yellow petroleum ethereal solution is washed there may be used, for example, the corresponding methyl, with water, dried over sodium sulfate and kept at 5 isopropyl, hexyl or cyclohexylesters. If 4-methyl-hexa- C. for 10 hours. It is then filtered by suction in order diene-(2.4)-al-(1) is used, there is obtained pure axeroto separate the deposited triphenyl phosphine oxide. phthene; by using 4-methyl-6-methoxy-hexadiene-(2.4)- From the filtrate all the constituents boiling below 100 al-(l) the vitamin A alcohol methyl ether is obtained. C. at 0.001 Torr. pressure are distilled off. The residue The new process permits the synthesis of compounds consists of vitamin A acid ethyl ester (A =351 to 353 of the vitamin A series in a very simple manner and remillimicrons, e=28,500 (in methanol)), from which by alkaline saponification 4.8 parts of vitamin A acid can be obtained as yellow needles of the melting point 181 to 182 C.

Example 2 To a solution of beta-ionylidene-triphenyl-phosphine in dimethylformamide, prepared from 20 parts of beta-ionol as in Example 1,-there is added a solution of 6 parts of gamma-methyl-sorbic aldehyde (=4-methyl-hexadiene- (2.4)-al-(1) in 20 parts of dimethylformamide. Reaction takes place with a rise in temperature and is completed after stirring for 2 hours without further supply of heat. It is then poured onto a mixture of ice and 10% phosphoric acid and extracted with petroleum ether. The petroleum ether solution is washed neutral with water, dried over sodium sulfate and kept for 12 hours at C. It is then filtered through a short column of aluminum oxide and the filtrate distilled. 4.3 parts of pure axerophthene of the boiling point 140 to 143 C. at 0.0 Torr. are obtained as a yellow viscous oil O 322 to 324 millimicrons, 38,000 (in hexane)) giving a red violet color with antimony chloride.

The true axerophthene thus obtained is diflerent from the retro-axerophthene of P. Karrer et al., see Helvetica Chimica Acta, vol. 35 (1952), p. 2570.

Example 3 A solution of 40 parts of phosphorus tribromide in 60 parts of absolute ether is gradually introduced at C. while stirring into a solution of 40 parts of beta-ionol in 250 parts of absolute ether. After stirring for 6 hours, it is poured onto ice and washed well with water. The washed ethereal solution of beta-ionyl bromide is shaken with parts of calcium chloride for 20 minutes, filtered and freed from solvent under reduced pressure at a maximum bath temperature of 35 C. The crude betaionyl bromide thus obtained is stirred into 45 parts of fused triphenyl phosphine, beta-ionyl-triphenyl-phosphonium bromide thereby being formed with spontaneous heating up to about 90 C. The yield amounts to about 100 parts.

Into the solution of this phosphonium salt in 200 parts of dimethylformamide there is gradually introduced a 10% methanolic solution of sodium methylate until a pH value of 7.9 is reached. Into the resultant dark violet solution of beta-ionylidenetriphenyl phosphine there is allowed to flow gradually while stirring a solution of 30 parts of 4-methyl-hexadiene- (2.4 -al- 1 -acid- 6 -ethyl ester in 30 parts of dimethylformamide. After heating for 60 minutes at 70 C., the methanol is distilled off in I vacuo and the dimethylformamide solution poured on a mixture of ice and 10% sulfuric acid while stirring. It is then extracted with petroleum ether; the extract washed neutral with water is dried with sodium sulfate for 5 hours at 5 C. After expelling the solvent there remain 50 parts of residue which consists substantially of cis-vitamin A acid ethyl ester.

The following procedures may be followed for isolating free cis-vitamin A acid from the reaction product or converting it into trans-vitamin A ester:

Cis-vitamin A acid.-- parts of the crude cis-ester obtained as above are dissolved in 150 parts of ethanol and boiled under reflux for minutes with 5 parts of potassium hydroxide dissolved in 10 parts of water. The ethanol and the unsaponifiable low molecular weight constituents are distilled off with steam. After acidification with 10% phosphoric acid, taking up the precipitated acid with ether and evaporating off the ether, 11 parts of pale yellow crystals are obtained which after recrystallization from methanol melt at 146 C. (A =33O millimicrons, e=4Z,000 (in methanol)); it accordingly consists of cisvitamin A acid.

Trans-vitamin A acid ethyl ester.--25 parts of the crude cis-ester obtained as above are distilled in a high vacuum, the trans-vitamin A acid ethyl ester (k =35l millimicrons, e=38,000 (in methanol)) passing over in a yield of 13 parts at to C. under a pressure of 0.005 Torr. The trans-vitamin A acid of the melting point 181 to 182 C. can be obtained therefrom by saponification as described above for the cis-acid.

What we claim is:

1. An improved process for the production of compounds of the vitamin A series which comprises mixing a beta-ionyl halide with a triarylphosphine, adding to the quaternary phosphonium halide formed by the interaction of the beta-ionyl halide and the triarylphosphine about an equivalent amount of a compound capable of binding hydrogen halide and selected from the group consisting of alkali metal alcoholates, alkaline earth metal alcoholates, alkali metal acetylides and alkali metal amides, splitting off of hydrogen halide, then mixing with the reaction mass an aldehyde of the general formula in which R represents a member of the group consisting of lower alkyl and carboxylic acid lower alkyl ester and separating the tertiary phosphine oxide from the reaction mixture.

2. An improved process for the production of vitamin A acid ethyl ester which comprises mixing beta-ionyl bromide with triphenyl phosphine, adding to the quaternary phosphoniurn bromide formed by the interaction of the beta-ionyl bromide and the triphenyl phosphine about an equivalent amount of a compound capable of binding hydrogen halide and selected from the group consisting of alkali metal alcoholates, alkaline earth metal alcoholates, alkali metal acetylides and alkali metal amides, splitting off of hydrogen bromide, then mixing with the reaction mass 4-methylhexadiene-(2.4)-al-(l)-acid-(6)- ethyl ester and separating the triphenyl phosphine oxide from the reaction mixture by filtration.

3. An improved process for the production of axerophthene which comprises mixing beta-ionyl bromide with triphenylphosphine, adding to the quaternary phospho nium bromide formed by the interaction of the beta-ionyl bromide and the triphenyl phosphine about an equivalent amount of a compound capable of binding hydrogen halide and selected from the group consisting of alkali metal alcoholates, alkaline earth metal alcoholates, alkali metal acetylides and alkali metal amides, splitting off of hydrogen bromide, then mixing with the reaction mass 4-methyl-hexadiene-(2.4)-al-(1) and separating the triphenyl phosphine oxide from the reaction mixture by filtration.

4. The process as claimed in claim 2 wherein the reaction of the quaternary phosphonium halide and said compound capable of binding hydrogen halide and also the reaction of said reaction mass and said ester are carried out in solution in dimethylformamide.

5. The process as claimed in claim 3 wherein the reaction of the quaternary phosphonium halide and said compound capable of binding hydrogen halide and also the reaction of said reaction mass and said ester are carried out in solution in dirnethylformamide.

References Cited in the file of this patent UNITED STATES PATENTS Isler Feb. 6, 1951 Isler et al. Ian. 7, 1958 OTHER REFERENCES 

1. AN IMPROVED PROCESS FOR THE PRODUCTION OF COMPOUNDS OF THE VITAMIN A SERIES WHICH COMPRISES MIXING A BETA-IONYL HALIDE WITHA TRIARYLPHOSPHINE, ADDING TO THE QUATERNARY PHOSPHONIUM HALIDE FORMED BY THE INTERACTION OF THE BETA-IONYL HALIDE AND THE TRIARYLPHOSPHINE ABOUT AN EQUIVALENT AMOUNT OF A COMPOUND CAPABLE OF BINDING HYDROGEN HALIDE AND SELECTED FROM THE GROUP CONSISTING OF ALKALI METAL ALCOHOLATES, ALKALINE EARTH METAL ALCOHOLATE, ALKALI METAL ACETYLIDES AND ALKALI METAL AMIDES, SPLITTING OFF OF HYDROGEN HALIDE, THEN MIXING WITH THE REACTION MASS AN ALDEHYDE OF THE GENERAL FORMULA 